PROJECT ABSTRACT The necessary complexity of neural tissues arises from a precise interplay between receptors and ligands found at the surfaces of neural cells. Accordingly, alterations of key extracellular binding events have been linked to psychiatric and neurodevelopmental disorders such as schizophrenia and autism spectrum disor- ders. Unfortunately, due in part to genetic redundancy, mutant mice lacking neural cell surface receptors often exhibit mild defects that belie the importance of a given receptor-ligand complex to the assembly of specific circuits. Without the benefit of genetic approaches to guide downstream biochemical analyses, extracellular neural protein-protein interactions remain understudied at the molecular level. Indeed, this is the case for contactins (CNTNs), which are a group of six immunoglobulin superfamily cell adhesion mol- ecules that are tethered to the cell membrane by a glycosylphosphatidylinositol anchor. CNTNs associate with structurally distinct cell surface receptors to participate in myelination, neural cell proliferation, axon guidance, and synapse formation. Unfortunately, a complete picture of the CNTN interactome is lacking and most of the molecular aspects of CNTN-ligand interactions remain elusive. Our recent studies have focused on the design of a robust in vitro screening assay to uncover po- tential interactions between extracellular neural receptors in general and CNTN/ligand pairs in particular. In this application, we will expand on our preliminary analysis of interactions between CNTNs, amyloid precursor proteins and the L1 family of cell adhesion molecules. We seek to combine biochemical and structural approaches to address the need for a molecular understanding of CNTN-ligand interactions. Thus, we propose to complete the following specific aims: (1) to identify the molecular basis for the inter- actions between CNTNs and amyloid precursor proteins and (2) to characterize interactions between CNTNs and the L1 family of cell adhesion molecules. These comprehensive molecular undertakings will lay a foundation to grasp the roles of CNTNligand complexes in neural networks. Overall, our contribution will be significant because it will broaden our grasp of a critical subset of extracellular interactions that underlie the formation and maintenance of the nervous system.